Hormone replacement therapy

All rapid responses

Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles.

Please correct in abovementioned publication the statement that paroxetine and fluoxetine are CYP2D6 inducers. Instead these SSRI are inhibitors of the CYP2D6 enzyme which participates in the transformation of the prodrug tamoxifen to its active metabolite endoxifen. The combination of paroxetine with tamoxifen in patients treated for breast cancer has been shown to result in an increase risk of death of breast cancer with increasing dose of tamoxifen (1). The combination of fluoxetine with tamoxifen had not been extensively studied yet. But on grounds of this plausible interaction mechanism, the combination of paroxetine and tamoxifen should indeed be avoided since alternatives for both the SSRI and tamoxifen are available.

In her BMJ podcast about HRT, Martha Hickey makes it clear that she thinks the WHI and MWS results have been “unpicked” and HRT can be a safe option for some women.1 Professor Klim McPherson has described such arguments as ridiculous.2 Important trials were stopped prematurely because of increases in cancers and vascular diseases – if they had been continued the results would have been worse. So why is HRT still being promoted?

Professor Jim Thornton, a former President of the Royal College of Obstetrics and Gynaecologists, notes that Hickey and colleagues have drug company interests; the effect on mortality from all causes is in the opposite direction when only randomised trials are included; and many women get withdrawal hot flushes on stopping HRT.3

Progestogens and oestrogens can be addictive and difficult to stop.4 Former GP Margaret White wrote, “the menopause nature gave me was fine but the one that Premarin gave me was hell!” HRT is also a major cause of mental illness with an increased risk of suicide.5

It is no longer believed that HRT prevents colorectal cancer with no benefit from either estrogen-alone or estrogen plus progestogen in the WHI clinical trial and observational study after 7 to 8 years of intervention and follow-up.6 Hazard ratios (95% confidence intervals) from the WHI observational study were 0.80 (0.53-1.20) for estrogen and 1.15 (0.74-1.79) for estrogen plus progestogen. Also there was no protective effect on colorectal mortality.

The bad effects of using progestogens and oestrogens are overwhelming:-

Thanks for your response. No, this is not an advert for HRT. We have tried to present an evidence based approach to managing troublesome symptoms at menopause. I agree that is difficult to provide risk benefit ratios for individual women, but this is what we need to do in clinical practice. WHI largely recruited asymtomatic women, so we would not expect HRT to improve quality of life. We did include information about recurrence of hot flushes after stopping HRT.

Many women do decide to live with their hot flushes. Others are unable to function and need treatment. We have tried to provide a balanced approach to both hormonal and non-hormonal strategies, and to non-pharmacological approaches such as CBT. There is now lots of information about HRT: good, bad and ugly. This helps women to make informed decisions about use, and our article is aimed at helping this decision.

Is this article an advertisement? I note the authors all have links with the HRT industry.

The claim of a dramatic reduction in hot flushes fails to mention symptom recurrence when the HRT is stopped, and that the largest trial (WHI) showed no benefit on quality of life.

The graphs appear to have been derived from, and give equal weight to, the largest randomised trial and the largest observational study. If the latter were removed and the other eight randomised trials included, the effect on all cause mortality would be in the opposite direction (odds ratio 1.06; 95% CI 0.94 -1.19) (Sanchez et al. 2005).

For the 51 year old woman with hot sweats, HRT provides short term relief. It increases the chance of some diseases, namely cardiovascular disease, strokes and breast cancer and reduces that of others, including osteoporosis, bowel cancer. The exact risk-benefit ratio varies with the woman's prior risk of each disease but the precision of the estimates is insufficient to allow individualised risk assessments.

When they learn that there is no overall improvement in quality of life, and that in the trials overall mortality was increased, most women wisely decide to live with their hot flushes.

I thought the article by Hickey et al. provided a comprehensive overview on the use of hormone replacement therapy in women with troublesome vasomotor symptoms.(1) I was surprised, however, that they failed to suggest low-dose oral progestogen as an alternative to HRT for menopausal symptoms. Medroxyprogesterone acetate (10mg) daily has been shown to be as effective as conjugated equine oestrogen (0.6mg) in controlling flushes and sweats
following surgical bilateral oopherectomy in premenopausal women.(2)

Martha Hickey and colleagues’ attempt to resurrect Hormone Replacement Therapy (HRT), by cobbling together selected data for 50 to 59 year olds from two disparate studies, still finds significant increases in breast cancer, strokes and venous thrombotic diseases.1

In reality women aged 50 to 59 cannot have a reduced overall mortality if they take HRT because cancers, vascular diseases and mental diseases are increased in women who take hormones at any age. Mortality was increased 3 fold in women under age 30 if they had ever taken oral contraceptives in the Royal College of General Practitioners study.2

Oral contraceptives were used previously by twice as many women taking oestrogen HRT than non-oestrogen takers in the Nurses’ Health Study. At baseline women who already had cancer were excluded, as were women who had coronary artery disease at each two yearly survey. By 1993 only 9% of the nurses enrolled were still taking HRT, 43% were taking vitamins and nine out of 10 did not believe that HRT was beneficial.3

Similarly HRT gave no overall benefit in the quality of life and doubled mortality from breast and lung cancers in the WHI randomised double blind trial.4,5 The Million Women Study found HRT doubled mortality from ovarian cancer.6

Simple physiological ways of avoiding vasomotor over-reactivity and osteoporosis at the normal physiological event of the menopause include repletion of measurable essential nutrient deficiencies and avoidance of masked food allergies, smoking, alcohol use and contributing medications. 7,8